The principal investigator (PI) is a head and neck oncologic and reconstructive surgeon who is passionate about improving treatment outcomes for patients with oral and pharyngeal squamous cell carcinoma (O/PSCC). The candidate's long-term goal is to become a successful translational surgeonscientist and, in that role, to advance the cellular and molecular understanding of 0/PSCC in order to discover, test and implement improved treatments. The proposed research is a collaboration between the Department of Otolaryngology-Head and Neck Surgery and the Cancer Center at the University of Virginia, an institution with a long, rich history of bioscientific discovery and an established track record in training physician-scientists. The principal investigator has recently shown that activation of the insulin-like growth factor-1 receptor (IGF1R) can compensate for epidermal growth factor receptor (EGFR) blockade in OSCC cells in vitro. Cells normally sensitive to EGFR antagonists appear resistant and continue their normal growth pattern when the IGF1R is activated during treatment. This is predominantly due to an increase in pro-survival signaling. Given the poor clinical effectiveness of these agents, the candidate hypothesizes that, in at least some O/PSCCs treated with targeted anti-EGFR therapy, alternate growth factor receptors such as the IGF1R can activate redundant or compensatory signaling cascades that permit continued tumor growth. Identification, elucidation, and interruption of such pathways will allow for development of more successful targeted therapies. The project will focus on determining the occurrence of IGFIR-induced resistance to EGFR antagonists in human tumor specimens and cell lines, and then will identify the pivotal signaling elements involved. The effectiveness of EGFFi/IGFIR co-inhibition will be tested in vivo in a primary xenograft library derived from human tumor biopsies, with the ultimate goal of proposing a new targeted therapy approach to O/PSCC. The candidate has proposed an extensive educational development plan. In addition to a variety of new research skills, he will take advantage of training opportunities in basic and translational science within the institution and in association with related national agencies. He will pursue coursework in the areas of clinical investigation, healthcare informatics, and in the responsible conduct of research. PUBLIC HEALTH RELEVANCE: Oral and pharyngeal cancers cause a significant number of deaths annually, and treatments are often debilitating and disfiguring. Responses to new anti-growth factor drugs are infrequent and brief. This proposal seeks to evaluate how often oral and pharyngeal squamous cell carcinomas evade these drugs by compensating with an alternate growth factor, and to determine if this mechanism of treatment resistance can be identified in advance and eliminated.